HE is an academic clinician in Medical Oncology and currently Professor of Clinical Cancer Medicine at the University of Cambridge, Department of Oncology and a Principal Investigator of the NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre. HPV infection results in production of virus-related proteins, which may induce de novo T cell response and more CD8+ T cell infiltration in tumor (43). Epidemiology. BMC Med. elective versus therapeutic neck dissection in node-negative oral cancer. 2017;5(10):42532. BMC Med. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. Turner NC, Ro J, Andr F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M, PALOMA3 Study Group. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. In fact, meta-analysis of melanoma neoadjuvant immunotherapy trials has shown that any degree of pathologic response and not just MPR/pCR, was correlated with better clinical outcomes (64). This trial highlighted the effectiveness of combination immunotherapy and chemotherapy for subsets of HNSCC patients. J Immunother Cancer (2021) 9(5):115. 2015;373(1):2334. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. Lancet Oncol. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. 2015;113(5):699705. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. For example, a phase II/III trial in patients with early-stage HPV-positive HNSCC is testing whether RT plus chemotherapy (cisplatin) or immunotherapy (nivolumab or durvalumab) can be used for de-intensification (NCT03952585, NCT03410615). Clin Cancer Res (2020) 26(13):32119. PD-L1 expression in tumor cells and immune cells remains the most widely used biomarker in HNSCC and other cancers (40, 41). Preoperative Chemotherapy in Advanced Resectable OCSCC: Long-Term Results of a Randomized Phase III Trial. chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. 2006;64(1):4756. Safety and Tumor Responses With Lambrolizumab (Anti-PD-1) in Melanoma. Exclusive: combination of drugs causes tumours to vanish in some terminally ill patients, study finds A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. SM does not have any conflict of interest to disclose. HE, SM and PR contributed equally to drafting, editing and revision of the manuscript. 2014;371(3):21323. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. This is a preview of subscription content, access via your institution. Google Scholar. Other work showed that PD-L2 expression was significantly correlated with PD-L1 expression in HNSCC clinical samples (42). In conclusion, the RESONATE-2 trial demonstrates that ibrutinib is a new important player in the treatment of elderly unfit patients and in those with high-risk disease. In phase 3 trials, ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, showed efficacy over traditional salvage therapeutic options in patients with relapsed or refractory CLL [32]. 2015;385(9980):187383. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Mdry R, Christensen RD, Berek JS, Drum A, Tinker AV, du Bois A, Gonzlez-Martn A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA, ENGOT-OV16/NOVA Investigators. In this trial, only one patient showed a grade III AE (rash) while no patients had grade IV AE, consistent with the safety and tolerability of neoadjuvant immunotherapy (75). University of Cambridge Department of Oncology, NIHR Cambridge Biomedical Research Centre, and Hon Consultant in Medical Oncology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK, Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100, Catanzaro, Italy, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781, Warsaw, Poland, You can also search for this author in J Cancer Res Clin Oncol (1997) 123(9):46977. CAS Copyright 2021 Shibata, Saito and Uppaluri. N Engl J Med. Platinum-Based Chemotherapy Plus Cetuximab in Head and Neck Cancer. Considering the TME will be dramatically changed after therapeutic treatment, neoadjuvant immunotherapy for HNSCC can provide an opportunity to establish immune markers to predict efficacy of subsequent immunotherapy. Table1 Completed neoadjuvant immunotherapy clinical trials. Park JW, Liu MC, Yee D, Yau C, van t Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA, I-SPY 2 Investigators. examined neoadjuvant 1) nivolumab (N) or 2) nivolumab plus ipilimumab (N+I) in untreated 29 oral cavity cancer patients in a phase II trial (eligible for T2 or node positive) (NCT02919683) (68). BMC Med. Harrington JA, Wheeler GM, Sweeting MJ, Mander AP, Jodrell DI. J Clin Oncol. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. https://doi.org/10.1007/978-3-030-14405-0_7, Tax calculation will be finalised during checkout. In the phase I setting, there is a pressing need to develop better trial methodologies for novel combinations, often of a standard chemotherapy with a novel targeted agent. doi: 10.1126/science.aar3593, 52. Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. The current results of anti-PD-1 therapy with pembrolizumab or nivolumab monotherapy in melanoma indicated a median overall survival (OS) of approximately 2years, but the combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) was shown to be superior in terms of progression-free survival (PFS) and OS (Table1) [11,12,13,14,15]. Readers are encouraged to refer to the full manuscript of these trials for a greater understanding. doi: 10.1002/cncr.33471, 22. Moreover, three anti-PD-1/anti-PD-L1 agents, pembrolizumab, nivolumab and atezolizumab, have been approved for second-line therapy of NSCLC [16,17,18]; however, contrary to melanoma, patient selection to therapy should be based on PD-L1 expression level of tumour cells. These trials led to US Food and Drug Administration (FDA) approval of the use of anti-PD-1 (nivolumab and pembrolizumab) for second-line for recurrent and metastatic HNSCC patients who had already experienced platinum-based therapies (31). J Clin Oncol. To determine the survival benefit of IC using docetaxel plus cisplatin and fluorouracil (TPF) regimen followed by CCRT, two-phase III randomized trials were completed: the PARADIGM trial reported in 2013 (19) and DeCIDE trial reported in 2014 (20). First, neoadjuvant immunotherapies will enhance systemic T cell responses for tumor-specific antigens before surgery (34). Another meta-analysis showed that HPV positive HNSCC patients display significant improved outcomes with PD-1/PD-L1 axis blockage treatment compared to HPV negative HNSCC patients (46). 2016;388(10043):48897. Lancet Oncol. There were excellent clinical outcomes and only one patient required adjuvant chemoradiation. Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, et al. Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR, Tsao A, Stewart DJ, Hicks ME, Erasmus J, Gupta S. The BATTLE trial: personalizing therapy for lung cancer. Status: Open - Recruiting. J Clin Oncol. 1. Hitt R, Grau JJ, Lpez-Pousa A, Berrocal A, Garca-Girn C, Irigoyen A, et al. J Clin Oncol. 2012;31:84552. Considering the treatment nave situation and the absence of treatment-resistant cells compared with the R/M setting, neoadjuvant immunotherapy is hypothetically likely able to result in a strong and durable therapeutic effect. 11:727433. doi: 10.3389/fonc.2021.727433. Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. The RTOG 90-03 trial compared four radiation therapy fractionation schemes for locoregionally advanced patients undergoing radiation therapy alone and is discussed. These data show that two doses or the longer neoadjuvant window (3 versus 6 weeks) resulted in an increased rate of pTR but did not increase the total proportion of patients with pTR. Recent developments in the classification of STS, insights into their molecular pathogenesis and the optimal treatment strategies have evolved considerably during the past decades and have led to the introduction of new therapies. This trial aims to enroll 600 patients. He has participated in several investigator-driven trials in melanoma and sarcoma. She is an Editorial Board Member for BMC Medicine. 2016;17(6):791800. Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. N Engl J Med. Patients received two cycles of drug therapy. No new safety signals were observed and there were no surgical delays. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol (2019) 37(15_suppl):25755. Delay to Surgery After Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma Affects Oncologic Outcomes. 2012;13(1):2532. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria Jr R, Conti I, Cosaert J, Schwartz GK. However, some immunological therapeutic effects can induce pseudo-progression or development of new lesions because of infiltration of immune cells into the primary tumor or lymph nodes, which makes it difficult to evaluate the treatment efficacy only with radiographical information (57). As opposed to the CIAO and IMCISION trials where some patients enrolled were undergoing salvage surgery, a third trial recently presented at ASCO 2021 focused exclusively on challenging recurrent, surgically resectable HNSCC patients (NCT03341936) (73). Head Neck. Schoenfeld JD, Hanna GJ, Jo VY, Rawal B, Chen YH, Catalano PS, et al. Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. Future Sci OA (2016) 2(1):Fso88. With the advent of novel oral agents that are well tolerated and highly efficacious, the therapeutic landscape of CLL underwent radical changes [31]. This was nearly double what we saw with one dose of pembrolizumab. Google Scholar. Am Soc Clin Oncol Educ Book (2020) 40:113. Cohen EEW, Soulires D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. 2013;14:25764. J Clin Oncol (2003) 21(2):32733. Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. A limited number of drugs have shown activity in advanced disease, and due to the rarity of these tumours, clinical trials in sarcoma include many subtypes and are mainly initiated by academic research groups. A clinical trial studying the side effects of chemotherapy for patients with locally recurrent head and neck squamous cell carcinoma. Study 19 [28, 29] used olaparib against placebo and demonstrated a PFS of 11.2months in BRCA-mutated patients compared with 4.3months for wild-type patients (hazard ratio, 0.18; P<0.0001). Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. doi: 10.1200/JCO.2019.37.15_suppl.TPS6090, 77. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece. Although a total of 21 patients experienced AEs, including grade 3/4 AEs in 2 (N) and 5 (N+I) patients, there were no surgical delays. 2016;32(18):28668. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazz D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. doi: 10.1136/jitc-2021-002568corr1, 68. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomized phase 3 trial.